U.S. Pat. No. 5,767,115 discloses the hypocholesterolemic activity of hydroxy-substituted azetidinones. Processes for preparing these compounds are described in U.S. Pat. No. 5,767,115, WO 97/16424, WO 97/45406, U.S. Pat. No. 5,886,171, WO 00/34240, J. Med. Chem. 1998, 41(6), 973–980 and J. Org. Chem. 1999, 64(10), 3714–18.
WO 00/34240 discloses an improved process for preparing these compounds, in particular ezetimibe, (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl) -3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone of formula I.
The reaction sequence of process for preparing ezetimibe is shown in scheme A.
The reduction of the ketone of the formula 3a
to give alcohol of formula 2a
involves the use of the reducing agent borane dimethyl sulfide in the presence of the expensive chiral catalyst (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c)(1,3,2) oxaza-borolidine.
U.S. Pat. No. 5,618,707 describes microbial reduction of compound of formula 3a to form the compound of formula 2a. The process requires strict control of cultures and chromatographic separations, which make the process unsuitable for industrial production.
We have discovered that less expensive (−)-DIP chloride ((−)-β-chlorodiisopinocampheylborane) can be used for such asymmetric reductions, thereby avoiding the use of expensive twin reagents i.e. borane dimethyl sulfide and (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo(1,2-c)(1,3,2)oxaza-borolidine, and avoiding the ‘difficult to handle’ reagents.
Thus the novel process is simple to handle and more economical than the known process.
The term lower alkyl refers to C1–C6 alkyl and the term lower alkoxy refers to C1–C6 alkoxy.
The object of the present invention is to provide a simple, cost effective process for the preparation of the ezetimibe intermediates.